A Novel Pyrazolo[3,4-d]pyrimidine Induces Heme Oxygenase-1 and Exerts Anti-Inflammatory and Neuroprotective Effects

Abstract

The anti-oxidant enzyme heme oxygenase-1 (HO-1) is known to exert anti-inflammatory effects. From a library of pyrazolo[3,4-d]pyrimidines, we identified novel compound KKC080096 that upregulated HO-1 at the mRNA and protein levels in microglial BV-2 cells. exhibited effects via suppressing nitric oxide, interleukin-1β (IL-1β), iNOS production lipopolysaccharide (LPS)-challenged It inhibited phosphorylation IKK MAP kinases (p38, JNK, ERK), which trigger inflammatory signaling, whose activities are by HO-1. Further, marker (Arg1, YM1, CD206, IL-10, transforming growth factor-β [TGF-β]) expression. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, lowered activation, protected nigral dopaminergic neurons, damage-associated motor deficits. Next, elucidated mechanisms induced AMPK its upstream LKB1 CaMKKbeta, pharmacological inhibition activity reduced on expression LPS-induced NO generation, suggesting KKC080096-induced upregulation involves LKB1/AMPK CaMKKbeta/AMPK pathway activation. caused an increase cellular Nrf2 level, bound Keap1 (Nrf2 inhibitor protein) with high affinity, blocked Keap1-Nrf2 interaction. This activation resulted concurrent induction other Nrf2-targeted antioxidant enzymes CATH.a These results indicate potential therapeutic for oxidative stress- inflammation-related neurodegenerative disorders such as Parkinson's disease.